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Helicobacter pylori

Introduction

Helicobacter pylori is a spiral-shaped bacterium that infects well over 30% of the world’s population. In some countries it infects more than 50% of the population. This is, therefore, one of the most common bacterial infections known to mankind. Between 1979-82, Australian pathologist, Robin Warren and Australian gastroenterologist, Barry Marshall, identified H. pylori and suggested a link to the development of stomach ulcers. Since this discovery, the World Health Organisation has declared the bacteria to be a Class 1 carcinogen (meaning the bacterium produces cancer). It invades the mucosal lining of the stomach and is the cause of up to 95% of duodenal and up to 75% gastric ulcers and has also been associated with gastric cancer and lymphoma.

Despite intense investigation into the spread of H. pylori, the precise mode of transmission remains unclear. There is some evidence to suggest that H. pylori is transmitted from person to person via the faecal-oral route yet the transmission mode remains unclear. Oral to oral or faecal to oral are the most likely routes at this stage. Most infections occur in childhood. Crowded living conditions, poor sanitation, poor personal hygiene and a poor water supply correlate with higher rates of infection (which can approach 80% of the population in the developing world).

H. pylori infects both genders equally. The presence of H. pylori in the stomach induces a chronic, active, inflammation in almost everyone infected. Majority of people with H. pylori, however, are asymptomatic. Fewer than 10% of individuals colonised with H. pylori develop peptic ulcer disease, gastric cancer or mucosa-associated-lymph-tissue (MALT) lymphoma.

History

The presence of spiral shaped micro organisms in the human stomach was described over 100 years ago by a Polish Clinical Researcher Prof W Jawroski at the Krakow Jagiellonian University. The presence of such bacteria was later confirmed in animals by G. Bizzazero but in spite of others noting the presence of these bacteria this infection was not really taken seriously until the late 1970s when Robin Warren a Pathologist in Perth noticed the appearance of these bacteria overlaying gastric mucosa in inflamed tissue when he examined histological specimens.

Warren saw that underneath the stomach’s thick mucous layer – a lining that coats the stomach's tissues and protects them from acid – bacteria are present in, almost exclusively, tissues that are inflamed. Wondering whether the microbes might somehow be related to the irritation he looked at the literature and learnt that German Pathologists had witnessed similar organisms in the past. But they had not been grown in culture and had been forgotten.

Barry was invited to start on this project of examining these bacteria but initially had difficulty growing the unknown bacteria in culture. He began his efforts in 1981 and by April 1982 the two men had attempted to culture samples from 30 patients all without success. Then, the Easter Holidays arrived; the hospital laboratory accidentally held some of the culture plates for 5 days instead of the usual two and on the fifth day growth of colonies on the culture plate were noticed. The workers called the bacteria Campylobacter pyloridis because they resembled pathogenic bacteria of the Campylobacter genus in the intestinal tract and they published the paper in 1983 reporting this finding. Later it was found that the bacteria did not fit the Campylobacter genus so a new genus called Helicobacter was created.

In an attempt to prove that the bacteria caused an ulcer Barry Marshall swallowed Helicobacter pylori culture in 1985 but did not develop an ulcer and only developed a severe case of gastritis – inflammation of the stomach. However the inflammation vanished without treatment. In this way Barry Marshall proved that Helicobacter pylori caused gastritis. At no time did he ever prove that Helicobacter caused Ulcer Disease. This was later derived from the understanding the treatment and eradication of H. pylori from patients with Duodenal Ulcer left them with a cure.

Borody at the Centre for Digestive Diseases in 1983 and 1984 commenced treating Helicobacter pylori in patients in whom endoscopically found the presence using a silver stain reported by pathologists from Douglass Hanly Moir Pathology Department. There was no specific cure available for Helicobacter pylori and it took over 36 different combinations of available antibiotics for Borody to finally come up with what was the first functioning Triple Therapy for eradication of H. pylori and cure of Duodenal Ulcer.

Marshall acknowledged this on his website and it is now commonly held that Marshall found the bug and Borody the drug. This combination comprised of Bismuth, Tetracycline and Flagyl. Initially it was Bismuth, Amoxicillin and Flagyl but a surgeon by the name of Michael Moont suggested the Tetracycline might work as Amoxicillin without the common allergy complaints that a percentage of patients had about Amoxicillin. Hence the combination finally settled on Bismuth, Tetracycline and Flagyl and with the help of Senator Edward Kennedy (see letter) by 1990 – a product called Helidac was launched on the US market combining the three antibiotics as the compliance pack medication of Borody’s invention patented back in 1985.

Marshall had previously patented a Double Therapy of Bismuth and an antibiotic which was supplanted by Borody’s invention of Triple Therapy which then swept America. In part, as a result of the availability of this antibiotic therapy physicians in the US and around the world began to believe that ulcers may well not be caused by acid and stress but by perhaps an infection. However, it was a slow road forward. Prof David Graham in the US was one of the early supporters and obtained a large NIH Grant to study Helicobacter. He supported Borody’s ideas and carried out multiple trials finally publishing and confirming the fact that eradication of Helicobacter results in the prevention of recurrence of the Duodenal Ulcer. Hence as a result of Warren, Marshall’s and Borody’s inventions we rarely see Duodenal Ulcer in advanced countries such as US and Australia where Helicobacter eradication has been carried out throughout the population of the countries. Indeed, the natural history of Ulcer Disease has been changed through the invention of Warren and Marshall teaching us that previously considered chronic inflammation caused by immune reactions may well be caused by an infection.

Later, improved versions of Triple Therapy emerged including the current one which contains Amoxil, Clarithromycin and a proton pump inhibitor. In Australia one version is called Klacid HP7. In the USA various companies have similar combinations on the market treating daily many patients with Helicobacter infection.

The next two inventions were carried out by Borody’s team at Five Dock coming out with a product on the US market taken through the FDA by Axcan Pharma and then titled Pylera. This was called Quad Therapy and it included Bismuth, Tetracycline, Metronidazole and a proton pump inhibitor. It overcame the problem of drug resistance and is now marketed throughout North America.

Finally, after completing his PhD on eradication failure, Borody came up with a number of protocols but the chief one is the use of Rifabutin, Amoxicillin and a high dose of proton pump inhibitor. This is a rescue or salvage therapy for those patients who had failed previous therapies and results in around 92% cure rate in those patients. As a result of treating so many patients in Australia with this infection – more than 22, 000 patients with H. pylori infection many of whom had ulcers at the Centre for Digestive Diseases alone – it is now rare for any surgeon to operate on recurrent Peptic Ulcer Disease. The only operations that are really carried out are those where there is a perforation or bleeding in patients who had previously not recognised that they had a Duodenal Ulcer.

Symptoms

Symptoms experienced by infected patients can include no symptoms at all, burning pain in the upper portion of the abdomen, indigestion, nausea, vomiting, burping and loss of appetite.

Diagnosis

There are many different tests used to diagnose H. pylori infection. Tests for H. pylori can be divided into two groups: a. invasive, which require upper gastrointestinal endoscopy (gastroscopy) and are based on the analysis of gastric biopsy specimens, and b. non-invasive.

Gastroscopy A Gastroenterologist may perform a panendoscopy (also known as a gastroscopy). This examination requires the patient to be sedated before an endoscope equipped with miniature video equipment is inserted through the mouth and down into the oesophagus. The Gastroenterologist can then take a biopsy (sample of tissue) for pathological testing to determine the presence of H. pylori infection. Histological diagnosis, whereby this tissue sample is examined under a microscope, is probably the gold standard. As well as confirming the presence of H. pylori, the pathological state of the stomach lining can be determined and defined as acute or chronic gastritis, atrophy, abnormal cells (metaplasia or dysplasia - precancerous changes), Barrett's oesophagus, or even lymphoma / malignancy. A rapid urease test may also be used to prove infection. These tests are known to achieve very high levels of accuracy. Culture of H. pylori can be carried out on such a tissue biopsy especially to determine sensitivity to particular antibiotics. This is of most importance in those who had failed the usual treatment and still carry the infection. In those patients sensitivity of H. pylori organism is tested for appropriate treatment to be commenced.

Urea Breath Tests Breath testing provides a rapid, non-invasive way of detecting the presence of active infection and is often used to check whether eradication has been successful. This test uses a sample of exhaled breath to determine infection. The principle of this exam relies on the ability of the bacteria to convert a compound called urea to carbon dioxide. When a specially labelled urea is ingested, the exhaled breath can be tested for labelled carbon dioxide. These tests are very accurate and easy to perform.

Serology Patients' blood may be screened for the presence of antibodies to H. pylori indicating an immune response to the bacteria. These tests are slightly less accurate than other available tests and do not discriminate between current infection and recent exposure. In those patients where the gastric lining has changed to the precancerous form of intestinal Metaplasia, neither biopsy nor Urea Breath Tests are able to be used as there are very few bacteria present. However serial serology from antibody concentrations can be used as follow up post treatment of Helicobacter infection.

Stool H.pylori Antigen Test This can be quite an accurate test and is one which is becoming used more frequently.

Complications

H. pylori has been strongly linked to the development of gastric and duodenal ulcers. Eradication of H. pylori can prevent ulcers forming. Indeed patients presenting with ulcers should be tested for H. pylori and treated because eradication of H. pylori in patients with pre-existing ulcers cures ulcer disease and can prevent most recurrences.

Gastric adenocarcinoma is the second leading cause of cancer death worldwide. There is strong evidence that H. pylori contributes to the development of gastric cancer. Many factors are likely to combine to cause cancer as only a tiny proportion of patients with H. pylori go on to develop gastric cancer. Diet low in fruit/vegetables, smoking, age and a high salt intake also increase the risk of gastric cancer, independent of H. pylori infection. However, of all these, it is H. pylori infection which is most closely associated with stomach cancer. Hence, due to its known association, all patients with H. pylori should be treated with antibiotics to prevent development of stomach cancer.

H. pylori infection can also lead to the development of a condition known as mucosa-associated-lymphoid-tissue (MALT) Lymphoma a type of cancer of the stomach. Treatment and eradication of H. pylori infection can result in regression of the malignancy in up to 75% of cases.

First Line Therapy

Treatment for H. pylori focuses on eradicating the bacteria from the stomach using a combination of organism-specific antibiotics with an acid suppressor and/or stomach protector. The use of only one or two medications to treat H. pylori is not recommended. Different countries have different approved treatments for H. pylori. At this time, a proven and effective treatment in Australia is a 7-day course of medication called Triple Therapy comprising two antibiotics, amoxicillin and clarithromycin, to kill the bacteria together with an acid suppressor to enhance the antibiotic activity. This regimen of triple therapy reduces ulcer symptoms, kills H. pylori and prevents ulcer recurrence in around 70% of patients but its efficacy is slowly falling.

With the use of antibiotics to treat so many patients with various conditions it has become more difficult to treat H. pylori due to increasing occurrence of antibiotic resistant strains. As a result, up to 35% of patients fail the first line therapy.

At the Centre for Digestive Diseases following failure of a treatment and at times on initial therapy, the combination regime is designed on a patient-by-patient basis, often dependent upon the antibiotic sensitivity profile of the infecting bacteria. With these tailored treatments our Gastroenterologists have successfully eradicated H. pylori from virtually all treated patients and in particular in many patients who have failed standard therapies.

Second line and subsequent therapies

In those patients who have been treated for H. pylori and the bacteria continues to be present, for example as determined by a Urea Breath Test, a further treatment using the previous therapy should not be tried again. At the CDD you will undergo a gastroscopy, have tissue samples collected and sent for culture. Your Gastroenterologist will construct a ”custom” antibiotic combination to eliminate this infection. From current results at the CDD even those with multiply failed therapies previously can expect around 90% success rate even with this resistant infection.

Research

At the Centre for Digestive Diseases, we are especially interested in developing eradication treatment alternatives effective in patients who have failed other standard therapies. These 'salvage' or 'rescue' therapies comprise varying combinations of three or more anti-H. pylori drugs. Treatment components which may be used may include Amoxicillin, Proton pump inhibitors, furazolidone, bismuth, Nitazoxanide, levofloxacin, as well as lactoferrin. Furthermore, the immunity of the gastric lining may need to be 'stimulated'- one of the current research projects in which it has been shown that some patients have an immune deficiency which contributes to eradication failure.

Resistant Helicobacter pylori -
How do we eradicate it?

Standard first-line treatment for H. pylori infection is marketed throughout Australia. Unfortunately once a patient has been treated using a standard first-line treatment, but fails to eradicate the infection, the H. pylori remaining can become resistant to a number of the antibiotics used. As such it is imperative that the patient is treated with different antibiotics to reduce the likelihood of creating a "super-resistant" infection.

At the Centre for Digestive Diseases we have developed a second-line treatment which we have seen a success rate of greater that 96% (published data), compared to re-treating with the same or similar first-line treatment which have a low success rate.

Our second-line treatments, which are adjusted to suit each patient based on the number and type of previous treatment, can include the following medications: Rifabutin, Bismuth subsalicylate Furazolidone, Lactoferrin, Nitazoxanide and Levofloxacin.